REGULATION OF CASPASE-8 Apoptotic cell death is orchestrated by the activation and functions of caspases. The defined apoptotic pathways (and presumably others as well) involve the oligomerization of specific adapter molecules, that in turn bind and oligomerize apical, or initator, caspases. These cleave and activate executioner caspases that then cause the biochemical and morphological changes associated with apoptosis by cleaving specific protein substrates in the cell. This component focuses on the activation, regulation, and function of the apical/initiator caspase-8 and its co-regulator FLIPL. Our central hypothesis on which the work is based is that caspase-8 is a monoiner that can only be activated by its enforced dimerization. and not by proteolytic cleavage. The studies described herein will explore the structural elements of caspase-8 activation, either by monomer-monomer association or through association with FLIPt. The regulation and function of the activated caspase will be analyzed in detail. In the context of the Program Project, the activation and function of caspase-8 is a key element in one of the two well-defined apoptotic pathways, the death receptor pathway, and probably in other lesser characterized pathways as well. With our changing understanding of the molecular activation of the initiator caspases, it is vital to explore how new views of caspase-8 activation and regulation affect our understanding of the function of this caspase in vivo.